Project Summary Brain metastases (BM) are the most common site of metastases from systemic cancer, with an incidence of up to 170,000 new cases per year in North America. Untreated BM patients generally live less than two months. Treatment options are currently limited to resective surgery, radiation therapies and chemotherapy. Thermal ablation has been postulated as an alternative therapy, but available devices have significant limitations with respect to conformal spatial control of ablation pattern and access to some regions within the brain. This project proposes development of needle-based therapeutic ultrasound (NBTU) devices and integrated system to accurately target and induce conformal ablation patterns for treatment of tumors and validation in a large animal model. The initial project period resulted in the development of a complete set of tools that utilize real-time magnetic resonance imaging guided robot-assisted (MRgRA) delivery of interstitial NBTU as a neuroablative device, which culminated in two swine survival surgeries to date. This NBTU device offers advantages over transcranial HIFU in that all regions of the brain can be targeted, ablation volumes can be shaped three- dimensionally, and concurrent biopsy is possible. This competitive renewal project will focus on the need to modify the device to prepare for first-in-human trials and to validate the device in a significant animal study. The objectives of this project are to: 1) Develop directional therapeutic ultrasound probes that are configured to produce controlled intensity distribution of energy along both length and angle to allow for conformal ablation patterns based on tumor volume. 2) Optimize the robotic delivery device design to maximize its reachable workspace, and validate this capacity by performing ablations in various brain regions. 3) Improve the interface between the current FDA 510K approved TheraVision therapy planning and monitoring system, MR thermal imaging (MRTI), and MR-guided robotic assist device to allow for ?point and click? software use; and 4) In accordance with FDA requirements for a first in man trial, validate the clinically ready version of this system under appropriate design controls by performing survival swine studies that monitor safety and accuracy. An FDA IDE application will be filed in the final stages of this project to prepare for a future first-in-human clinical trial. Successful completion of this project will result in substantial technical and feasibility advancements over the current state-of-the-art for HIFU, including volumetric MR thermal imaging and customized NBTU probes and dosing strategies. This project will lead directly to delivery of a new high-precision treatment option for patients with brain metastases that will provide targeted tumor ablation with minimal collateral damage to surrounding non-targeted tissue.